Ординатура / Офтальмология / Учебные материалы / Uveitis Text and Imaging Text and Imaging Text and Imaging 2009

CONCLUSION

CNV related to intraocular inflammatory diseases is a rare but severe complication of uveitis. In most cases the combination of FA, ICGA and OCT allows to precisely determine the characteristics of the neovascular membrane. In case of active inflammation an infectious aetiology should be looked for to include specific therapy if available. In both infectious and noninfectious active uveitis with CNV the first step should be aimed at controlling inflammation with the help of corticosteroids, usually given systemically but sometimes also locally in unilateral disease, and/or immunosuppressants. In CNV associated with inactive inflammatory disease, corticosteroids with or without immunosuppressants is also the first move as subclinical inflammatory events can be present and trigger CNV.119,120 However no time should be lost to resort to additional therapies aimed directly at the neovascular process. Some CNV respond to anti-inflammatory or immunosuppressive therapy alone. If no response is obtained, therapy directly aimed at the neovascular process should be decided upon. Argon laser photocoagulation should probably be avoided even in CNV outside the fovea as easily performed intravitreal administration of anti-VEGF therapy, such as Avastin®, seems to show an overwhelming effect. These results are however still only based, as for all other methods evaluated, on case reports or small series. Similarly PDT seems to be no match to Avastin® and common sense directs the clinician to use these new types of therapy.

KEY POINTS

1.Uveitic CNV is a severe sequela occurring in posterior pole intraocular inflammation.

2.The disease can be secondary to both infectious and noninfectious uveitis.

3.The pathophysiology is still not known and is one of the key points of modern ophthalmic research.

4.The prevalence and incidence of such sequela is not easily evaluated.

5.Fluorescein angiography is a useful tool for the evaluation of CNV activity, and to better evaluate the position to the fovea.

6.Indocyanine green angiography is important for the assessment of choroidal involvement, but it is not contributory to the evaluation of CNV activity. This tool is mandatory for the modulation of medical therapy: the

medical treatment is based on both the clinical appearance of choroid and the CNV activity.

7.OCT is very useful in assessing the activity of CNV by detecting intraretinal and subretinal fluid and in monitoring response to treatment.

8.Infectious uveitis can rarely have CNV as a late sequela, and the majority of reports are anecdotal; the therapy is based on a clinical rationale, combining specific medical therapy and other techniques, such as lasers, intravitreal drugs and, rarely, surgery.

9.CNV associated with toxoplasmosis is a relatively common clinical situation

10.CNV can be a common occurrence in some types of noninfectious uveitis, such as punctate inner choroidopathy, multifocal choroiditis and serpiginous choroidopathy.

11.The treatment for CNV secondary to non-infectious uveitis is based on the medical therapy, generally steroids and immunesupressants, combined with other tools, such as lasers, intravitreal anti-VEGF drugs and surgery.

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INTRODUCTION

Macular oedema represents a common pathological end stage of several retinal and choroidal diseases.1 Inflammatory macular oedema in particular can be related to various clinical entities such as pars planitis and posterior uveitis due to various granulomatous etiologies like sarcoidosis, tuberculosis, syphilis and cytomegalovirus.2,3 Furthermore, inflammatory macular oedema is associated with postoperative inflammation after ocular surgery4 while other causes include retinitis pigmentosa5 and immune recovery syndrome.6

HISTORICAL DISCOVERY OF INFLAMMATORY MACULAR OEDEMA

At the end of the first World War, the Swiss ophthalmologist Alfred Vogt was the first to describe in detail the appearance of macular oedema in uveitis (Figure 1) and in other conditions such as the progression from

macular cysts to a macular hole7-9 (Figure 2). However, it appears that the inflammatory origin of macular oedema was already suspected by Leber in 1877.8,10 The Austrian ophthalmologist Karl Hruby was the first to draw attention to the development of macular oedema after cataract extraction in 1950.11 Three years later Irvine published his classical paper on cystoid macular oedema (CMO) after intraand extracapsular cataract extraction describing the vitreous tug syndrome of incarcerated vitreous in the corneal wound.12 The classical petaloid picture on fluorescein angiography was finally published by Gass in 1966.13

THE BLOOD-RETINAL BARRIER

The key player who decides whether or not macular oedema will occur is the Blood-Retinal Barrier (BRB), the understanding of which is crucial to fully comprehend both the pathophysiology and the possible treatment options of macular oedema.

ANATOMY OF THE BRB

The blood retinal barrier consists of an inner barrier, which is formed by the zonulae occludentes and adhaerentes of endothelial cells of retinal vessels. These structures do not permit a passive fluid egress from the vessel lumen into the retina. Perivascular astrocytes and pericytes are responsible for the continuous maintenance of the inner BRB.14,15 The relatively small amount of astroytes in the area of the fovea – compared to other areas of the retina – is a potential explanation for the evolution of macular oedema in this area.16

The outer BRB is composed of the zonulae occludentes and adhaerentes of the retinal pigment epithelium cells (RPE). The polarised distribution of membrane-bound proteins on the apical and basal cell membrane is responsible for the barrier function17,18 (Figure 3).

The molecular structure of the zonula occludentes (tight junctions) is formed by at least eight proteins, which are ankered in the peripheral cytoplasma and in the plasma membrane of the endothelial cells and the RPE. These proteins function as a complex to regulate the paracellular permeability.19 Occludin, which has 4 transmembrane domaines, is the main protein of the tight junctions. Occludin is coupled with

Figure 3: Schematic diagram of the blood-retinal barrier (BRB) showing the inner BRB, which is composed of the endothelial cell layer of the retinal vessels, whereas the outer BRB is composed of the tight junctions in the RPE. (ILM: internal limiting membrane, ELM: external limiting membrane, RPE: Retinal pigment epithelium)

the zonula occludens proteins ZO-1 and ZO-2. The zonula adhaerens comprises cadherin, which is in turn connected to other proteins such as catenin and in particular with the actin cytoskeleton of the cell (Figure 4).

PHYSIOLOGY OF THE BRB

The BRB acts as a selective barrier between the retina and blood circulation of the retina and the choroid.

Figure 4: Detailed schematic diagram of the tight junction between two retinal endothelial cells showing the transmembrane occluding protein, which is in part responsible for the tightness of the blood retinal barrier. The protein is anchored in the cytoskeleton through Zonula Occludin protein 1 (ZO-1). This complex is also called Zonula occludens. The Zonula adhaerens, which shows less tightness than the Zonula occludens, is composed of several proteins such as Cadherin and Catenin, which are linked with the cytoskeleton via Myosin and Actin filaments

This system allows the neurons of the retina to function in a protected environment.20 There are several mechanisms of balancing osmotic forces, ion conentrations as well as glucose and amino acids. The physiological function of the outer BRB in the RPE is on one side the inhibition of fluid flow from the choroid into the subretinal space, and on the other side a continuous fluid transport from the subretinal and intraretinal space into the choroid.21 Roughly 70 percent of this transport is effected through several different active molecular transport systems.22,23 The RPE uses the same intercellular adhesion molecules (ICAMs) for local immune reactions as does the retinal endothelium. It is thus a common location for inflammatory processes which can lead to a break down in BRB function.24 Both barriers also protect the retina from invasion by immunoglobulins and circulating cells of the immune system.25

ANATOMY AND PATHOPHYSIOLOGY OF INFLAMMATORY MACULAR OEDEMA

ANATOMY OF INFLAMMATORY CYSTOID MACULAR OEDEMA

The classic understanding has been that cystoid spaces form within Henle’s layer. In the foveal region, these

Figure 5: Histopathological specimen of a cystoid macular oedema due to posterior uveitis related to cytomegalovirus. The intraretinal cysts are distributed throughout all the different layers of the retina with a predilection for the fovea. Haematoxylin/Eosin stain (courtesy of Dr. Sylvie Uffer)

fibers of the outer plexiform layer demonstrate a loose arrangement allowing accumulation of fluid leaking from perifoveal capillaries. The absence of Müller cells in the foveal region is also a contributing factor furthermore explaining the predilection of CMO to the macular region.1 However, it has been shown that the cystoid spaces can also form in the outer nuclear, inner nuclear, inner plexiform, and even the ganglion cell layer (Figure 5). The specific layers involved depend on the underlying disease.26 Cystoid spaces in CMO are intracellular or extracellular or both according to different pathologic studies.27-29

PATHOPHYSIOLOGY OF INFLAMMATORY CYSTOID MACULAR OEDEMA

Breakdown of the blood-retinal barrier with consecutive fluid retention and protein accumulation within the retina can be caused by multiple mechanisms.30,31 Changes in permeability develop particularly in regard to the paracellular spaces32 and the major agents are growth factors such as Transforming Growth Factor beta (TGFb) and Vascular Endothelial Growth Factor (VEGF). The RPE cells are particularly susceptible to inflammatory cytokines which cause a breakdown of the blood-retinal barrier.33-36 In this context ICAMs may play an important role, and increased ICAM-1 levels were found in the presence of macular oedema.37

Experimental studies have also shown that Inter- feron-gamma and Tumor-Necrosis-Factor-alpha reduce the transepithelial resistance of the RPE cells.37 Histamine and glucose reduce the production of the zonula occludens protein 1 (ZO-1) and glucose decreases in addition to the expression of occludin,38 both

very important proteins in the maintenance of BRB integrity. These different factors may also synergistically work together in a cascade to influence BRB integrity39 (Figure 6).

In the context of intraocular inflammation, the outer BRB appears to be more affected than the inner BRB. Secondary involvement of the inner BRB can however occur.39

The barrier function of the BRB can be restored by the eye itself, if the inflammatory stimulus is only of limited duration.40 However, if inflammation persists, focal or diffuse leakage of fluid into the extracellular space of the retina will result. This fluid will lead to macular oedema, macular cysts and if severe to serous detachment of the neuroretina.41,42

EPIDEMIOLOGY AND CLINICAL MANIFESTATIONS OF INFLAMMATORY MACULAR OEDEMA

Cystoid macular oedema represents a major cause of visual loss in uveitis.43-45 Durrani et al45 in a retrospective study of 315 patients with uveitis reported that visual loss was related to CMO in 47 percent of cases. In another large cross-sectional survey of 581 patients with uveitis, CMO was noted in 33 percent of cases where CMO was considered the cause of visual loss in 42 percent of the cases.43 In that study, poor visual acuity in patients with CMO was associated with an advanced age of the patients, chronic inflammation, and various specific uveitis entities such as birdshot

chorioretinopathy. Loss of visual acuity due to CMO may be irreversible due to a permanent loss of photoreceptor cells.46

Cystoid macular oedema however not only occurs as part of uveitis, but it also associated with any ocular surgery, most commonly with cataract extraction.

Postoperative CMO is thought to be an inflammatory process47 and is the most frequent cause of decreased vision in patients following cataract surgery.48 Clinically significant CMO has a reported incidence of 1 to 2 percent after cataract surgery.4 Angiographic CMO is more common and has been reported to occur after about 20 percent of cataract surgeries.49,50 However, these figures may be lower today given the technical advances in phakoemulsification and the reduced surgical trauma during the intervention. The incidence of angiographic macular oedema 6 weeks following pneumatic retinopexy and scleral buckling surgery has been reported to be 11 percent and 29 percent, respectively.51 CMO may also complicate hereditary retinal degenerations such as retinitis pigmentosa with a reported incidence between 3 percent and 15 percent.5,52 CMO related to immune recovery syndrome in AIDS patients receiving highly active antiretroviral treatment has also been reported between 19 and 22 percent.53

CLINICAL SIGNS OF INFLAMMATORY MACULAR OEDEMA

Macular oedema can be detected with indirect ophthalmoscopy as tiny cysts arranged like the petals

of a flower around the foveola. Ophthalmoscopically, the cysts are characterized by an altered light reflex with a decreased central reflex and a thin, highly reflective edge. These changes may be better visible using green light. A thorough examination of the anterior segment should always complement the clinical evaluation as incarcerated vitreous or a badly placed intraocular lens may be the underlying cause of inflammatory macular oedema.

Apart from distance visual acuity loss, contrast sensitivity, color vision, reading acuity and reading speed are also compromised in patients presenting CMO.44,54,55 Additionally, a marked reduction in central retinal sensitivity with either a relative or absolute scotoma during active macular oedema, but also after the oedema has resolved, has been reported.56 Retinal thickness appears to be most closely correlated with visual acuity57 whereas increased leakage on fluorescein angiography is not directly correlated with reduced visual acuity.

IMAGING OF INFLAMMATORY CYSTOID MACULAR OEDEMA

FLUORESCEIN ANGIOGRAPHY

The fundus fluorescein angiography (FA) has for many years been one of the most readily available and useful tests in detecting macular oedema of various etiologies. FA demonstrates the diffuse capillary leakage with pooling in the cystoid spaces.58 The amount of fluorescein leakage depends on the dysfunction of the retinal vascular endothelium and there is a significant correlation between visual acuity and the area covered by these cystoid changes.1,29 So called “silent” angiograms have also been reported, which correspond to the presence of clinical macular oedema which shows however no leakage on FA. The underlying reason for this may be very old changes within the retina, which are characterized by intraretinal cysts, which have become impermeable to the fluroescein dye diffusion. FA can confirm the diagnosis in most instances, however, the classic petaloid pattern is not always seen on fluorescein angiography and it is often difficult to ascertain the exact origin of the leakage in the outer layers of the retina since it can be obscured by inner retinal leakage (Figures 7A and B). Furthermore, fluorescein angiographic images in patients with

Figure 7A: Early frames of a cystoid macular oedema 3 months following a phacoemulsification complicated by a break in the posterior capsule during surgery. Note the classic “petaloid” pattern of hyperfluorescence as the dye accumulates in the cystoid spaces. Also note the slight leakage at the level of the optic nerve. Visual acuity 6/60

Figure 7B: Late frames of the same eye showing increased leakage of fluorescein dye into the parafoveal cystoid spaces with more widespread diffuse leakage around the optic nerve. Visual acuity 6/60

retinitis pigmentosa, who show important pigmentary changes in the fundus, may be very difficult to interprete. Indocyanine green angiography is not useful for the evaluation of macular oedema as the origin of the leakage is found in the retinal and not in the choroidal vascular bed.

Figure 8: Optical Coherence Tomography of an inflammatory postoperative cystoid macular oedema showing multiple cysts in the perifoveal region. Also note the small serous retinal elevation subfoveally

OPTICAL COHERENCE TOMOGRAPHY (OCT)

Optical coherence tomography (OCT), which can perform micron resolution tomographic cross-sectional imaging of biological tissues, is able to accurately measure the retinal thickness allowing a more precise and reproducible assessment than FA.59-61 OCT appears to be particularly useful for imaging uveitic cystoid macular oedema as these patients can have important posterior synechiae that impede sufficient dilation for fundus examination or flusorescein angiography (OCTs can be performed in non-dilated eyes)60 (Figure 8).

OCT has been used to investigate the correlation of retinal thickness and visual acuity, and it has been shown that distance visual acuity was negatively correlated with retinal thickness, the presence of cystoid macular oedema, and the presence of a serous retinal detachment in patients with uveitis.62 In one study, retinal thickness as measured by OCT appeared to be better correlated to reading (near) acuity and reading speed than distance visual acuity.44 In an effort to categorize CMO in inflammatory ocular conditions such as uveitis, OCT has been helpful to demonstrate 3 possible image patterns in uveitis: diffuse macular oedema, cystoid macular oedema, and serous retinal detachment.62 It is however not yet clear what the underlying pathophysiological mechanisms of these three types are. Furthermore, OCT is not only useful to diagnose and classify inflammatory macular oedema, but its most important impact is on the clinical followup of patients who have received treatment for the

macular oedema. Treatment response can be measured in fast and non-invasive way using OCT, which marks a big advantage to the previous widespread use of fluorescein angiography for this purpose.63

Recently a new generation of high-speed and ultrahigh-resolution three-dimensional OCT has become available which offers an even more advanced assessment of macular oedema with a particular efficacy in the volumetric analysis of uveitic macular oedema.64

Other examination techniques which may be useful in the imaging of inflammatory macular oedema include the retinal thickness analyzer that can generates a three-dimensional reconstruction of the retina offering a detailed map of retinal thickness65 and the scanning laser ophthalmoscope that provides quantitative analysis of retinal thickness and macular cystoid structures.66,67

TREATMENT OF INFLAMMATORY CYSTOID MACULAR OEDEMA

MEDICAL TREATMENT

Treatment of inflammatory macular oedema demands a graded and systematic approach to prevent irreversible visual loss.68 First line medical treatment options include non-steroidal anti-inflammatory agents (NSAIDs), carbonic anhydrase inhibitors (CAIs), and steroids. Corticosteroids may be administered topically, by periocular or intravitreal injection, orally and parenterally. Immunomodulators and AntiVEGF agents may also been used in the treatment of inflamatory macular oedema. Steroids and NSAIDS interact with the breakdown of membrane lipids as shown in Figure 9.

Non-steroidal Anti-inflammatory Drugs (NSAIDs)

The action of NSAIDs is based on the inhibition of the enzyme cyclo-ogygenase, which in turns inhibits the production of prostaglandins in the eye, which are produced as a degradation product of arachidonic acid.69 Some NSAIDs also act on other mediators. Diclofenac sodium, for example, inhibits in high doses the formation of leukotrienes which amplify cellular infiltration during an inflammatory reaction.70 Nonsteroidal inflammatory drugs have also been shown to modulate choloride movement, and as a consequence fluid movement, through the RPE.71